Pharmaceutical formulations suitable for parenteral delivery typically comprise (a) an active molecule; (b) a buffering agent with sufficient buffering capacity to control solution pH; and (c) a tonicity agent to provide isotonicity of the formulation. Additionally, further components may be added such as antioxidants, specific stabilizers, surfactants, preservatives, etc., as needed depending on the specific active and its intended use.
The selection of the formulation components has to be based on thorough studies evaluating different components with respect to their function in the formulation and optimal stabilizing capacity. Furthermore, other formulation studies have to be performed to identify other solution parameters, such as optimal pH and ionic strength for the specific active molecule and its intended use. Studies are also performed to optimize the concentrations of the respective formulation components. In many cases, additional aspects of the final formulation and its clinical use have to be considered, such as appropriate injection volume, compatibility with physiological fluids or tissues, viscosity, local tolerance etc.
One example of local tolerance concerns the selection of buffer species. It is known that specific buffer species may provoke local in-tolerance or injection pain. Sodium citrate has been reported to cause pain upon subcutaneous injection in some cases (Frenken, 1993, Laursen, 2006). In addition, buffer concentration should be minimized to be optimal with respect to not only to pH stability in the drug formulation during long term storage, but also as having minimal impact on the physiological conditions at the injection site (e.g. Fransson and Espander-Jansson, 1996).
The list of components that can be added to a formulation for parenteral delivery is limited (Wang and Kowall, 1980; Nema, 2006). A number of aspects has to be considered; safety, prior experience in humans, availability from suppliers, etc. The stability of protein drugs in vivo and in vitro is a complex matter where multiple degradation reactions occur in parallel, such as oxidation, deamidation, aggregation etc. One major reaction occurring is formation of aggregates. Protein aggregates can form via covalent or non-covalent pathways, and can be of soluble or insoluble nature. The presence of protein aggregates is a major concern from safety perspective as it may impact the secondary and tertiary structure of the protein. Presence of specific non-native protein structures has been associated with increased immunogenicity of proteins potentially causing reduced efficacy or even in vivo immunological reactions to native proteins, with life threatening conditions as result.
Interleukin-1 mediated diseases include rheumatoid arthritis (RA), inflammatory bowel disease (IBD), sepsis, sepsis syndrome, osteoporosis, ischemic injury, graft vs. host disease, reperfusion injury, asthma, insulin diabetes, myelogenous and other leukemias, psoriasis and cachexia. These and other inflammatory diseases are characterized by the production of cytokines, including interleukin-1.
For those syndromes where a role for IL-1 in the pathology of the disease has been established, the clinical manifestations of the disease can rapidly be alleviated by treatment with anti-IL-1 medicines. One such medicine is Kineret®, whose active component, anakinra, is a recombinant version of the naturally occurring IL-1 receptor antagonist (IL-1ra). Anakinra is disclosed in, e.g. U.S. Pat. No. 5,075,222.
Kineret® (anakinra for injection) is formulated at 150 mg/ml with a 10 mM sodium citrate buffer (pH 6-7) and sodium chloride (140 mM) as tonicity agent. Furthermore, 0.5 mM EDTA and 0.1% (w/w) polysorbate 80 are used as stabilizers. The selection of sodium citrate as buffer component for anakinra was based on detailed studies evaluating the short and long term stability of anakinra at real time conditions. Several potential buffer components were evaluated, sodium phosphate being one and sodium citrate was identified as providing the optimal stability with respect to anakinra aggregation (Raibekas et al., 2005). Aggregation of anakinra was a major concern for the selection of the buffer component. The concentration of the sodium citrate was minimized as much as possible considering the local tolerability.
During clinical use of anakinra in 10 mM sodium citrate, it was found that the formulation caused issues with local tolerance at the subcutaneous injection site (Thaler, 2009). Injection site reactions are not uncommon with subcutaneous delivery of protein drugs and are a general problem (Haller, 2008) and are associated with clinical use of a large number of protein drugs. More than 50% of the patients using anakinra for injection experiences injection site reactions to some degree for the first injections. The nature and the mechanism of local reaction have been investigated and several conclusions have been made (Bendele, 1995). It has been concluded that the injection site reaction has multiple causes including anakinra molecule itself and the formulation components, sodium citrate having a very large impact.
Consequently, there is a need for anakinra compositions, suitable for injection, which are stable and which avoid the drawbacks with anakinra compositions comprising sodium citrate.